ularitide and Heart-Failure

Acute decompensated heart failure (ADHF) has a poor prognosis and limited treatment options. No direct comparisons between ularitide-a synthetic natriuretic peptide being evaluated in ADHF-and other vasoactive substances are available. The aim of this meta-analysis was to determine haemodynamic effect sizes from randomized double-blind trials in ADHF.. Eligible studies enrolled patients with ADHF requiring hospitalization and haemodynamic monitoring. Patients received 24-48 h of infusion with a vasoactive substance or comparator. Primary outcome measure was pulmonary artery wedge pressure (PAWP). Treatment effects were quantified as changes from baseline using mean differences between study drug and comparator. Results were analysed using random-effects (primary analysis) and fixed-effects meta-analyses. Twelve randomized, double-blind studies were identified with data after 3, 6, and 24 h of treatment (n = 622, 644, and 644, respectively). At 6 h, significant PAWP benefits for ularitide over placebo were seen (Hedges' g effect size, -0.979; P < 0.0001). On meta-analysis, treatment difference between ularitide and pooled other agents was statistically significant (-0.501; P = 0.0303). Effect sizes were numerically higher with ularitide than other treatments at 3 and 24 h. After 6 h, a significant difference in effect size between ularitide and all other treatments was observed for right atrial pressure (Hedges' g, -0.797 for ularitide and -0.304 for other treatments; P = 0.0274).. After 6 h, ularitide demonstrated high effect sizes for PAWP and right atrial pressure. Improvements in these parameters were greater with ularitide vs. pooled data for other vasoactive drugs.

Topics: Acute Disease; Atrial Natriuretic Factor; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Heart Failure; Hemodynamics; Humans; Peptide Fragments; Randomized Controlled Trials as Topic

Topics: Atrial Natriuretic Factor; Blood Pressure; Diuretics; Global Health; Heart Failure; Humans; Infusions, Intravenous; Peptide Fragments; Prognosis; Survival Rate

Heart failure with reduced ejection fraction (HFrEF) is a progressive disorder whereby cardiac structure and function continue to deteriorate, often despite the absence of clinically apparent signs and symptoms of a worsening disease state. This silent yet progressive nature of HFrEF can contribute to the increased risk of death-even in patients who are 'clinically stable', or who are asymptomatic or only mildly symptomatic-because it often goes undetected and/or undertreated. Current therapies are aimed at improving clinical symptoms, and several agents more directly target the underlying causes of disease; however, new therapies are needed that can more fully address factors responsible for underlying progressive cardiac dysfunction. In this review, mechanisms that drive HFrEF, including ongoing cardiomyocyte loss, mitochondrial abnormalities, impaired calcium cycling, elevated LV wall stress, reactive interstitial fibrosis, and cardiomyocyte hypertrophy, are discussed. Additionally, limitations of current HF therapies are reviewed, with a focus on how these therapies are designed to counteract the deleterious effects of compensatory neurohumoral activation but do not fully prevent disease progression. Finally, new investigational therapies that may improve the underlying molecular, cellular, and structural abnormalities associated with HF progression are reviewed.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Apoptosis; Atrial Natriuretic Factor; Biphenyl Compounds; Calcium; Disease Progression; Diuretics; Drug Combinations; Fibrosis; Heart Failure; Humans; Mitochondria, Heart; Myocardium; Myocytes, Cardiac; Natriuretic Agents; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Stress, Mechanical; Stroke Volume; Tetrazoles; Valsartan; Ventricular Dysfunction, Left

Despite advances in therapy, patients with heart failure (HF) continue to experience unacceptably high rates of hospitalization and death, as well as poor quality of life. As a consequence, there is an urgent need for new treatments that can improve the clinical course of the growing worldwide population of HF patients. Serelaxin and ularatide, both based on naturally occurring peptides, have potent vasodilatory as well as other effects on the heart and kidneys. For both agents, phase 3 studies that are designed to determine whether they improve outcomes in patients with acute HF have completed enrollment. TRV027, a biased ligand for the type 1 angiotensin receptor with effects that extend beyond traditional angiotensin-receptor blockers is also being studied in the acute HF population. Omecamtiv mecarbil, an inotropic agent that improves myocardial contractility by a novel mechanism, and vericiguat, a drug that stimulates soluble guanylate cyclase, are both being developed to treat patients with chronic HF. Finally, despite the negative results of the CUPID study, gene transfer therapy continues to be explored as a means of improving the function of the failing heart. The basis for the use of these drugs and their current status in clinical trials are discussed. (Circ J 2016; 80: 1882-1891).

Topics: Angiotensin II Type 1 Receptor Blockers; Atrial Natriuretic Factor; Clinical Trials as Topic; Heart; Heart Failure; Humans; Kidney; Oligopeptides; Peptide Fragments; Recombinant Proteins; Relaxin; Vasodilation

An estimated 5.1 million Americans have chronic heart failure and this is expected to increase 25% by 2030. Heart failure is a clinical syndrome that evolves from either functional or structural changes to the ventricles that lead to filling or ejection abnormalities. Thus far, pharmacotherapy has been show to be beneficial in patients only with reduced ejection fraction; however, new therapies have been developed in hopes of reducing the burden of heart failure. In this review, we will discuss current pharmacotherapies recommended in American College of Cardiology/American Heart Association guidelines, the evidence behind these recommendations as well as new and emerging therapies that have been developed.

Topics: Adrenergic beta-Antagonists; American Heart Association; Amides; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Biphenyl Compounds; Calcium Channel Blockers; Cardiology; Cardiotonic Agents; Cardiovascular Agents; Digoxin; Diuretics; Drug Combinations; Erythropoietin; Evidence-Based Medicine; Fumarates; Heart Failure; Hematinics; Humans; Hydralazine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Isosorbide Dinitrate; Ivabradine; Mineralocorticoid Receptor Antagonists; Peptide Fragments; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Societies, Medical; Stroke Volume; Tetrazoles; United States; Valsartan; Vasodilator Agents

Brain natriuretic peptide (BNP), also known as a B-type natriuretic peptide, is one of the important biomarkers with a proven role in the diagnosis of congestive heart failure (CHF). Researchers from the different clinical field have researched into the performance features of BNP testing in the acute care set-up to assist and improve in diagnosing CHF and in predicting future morbidity and mortality rates. The potency of BNP has also been researched into in cases like myocardial ischemia and infarction, cor pulmonale, and acute pulmonary embolism (PE). Based on their vaso-dilatory and diuretic properties and ability to inhibit renin-angiotensin-aldosterone system, natriuretic peptides are able to provide an efficient technique and mechanism of action in the pathophysiologic framework for CHF treatment and management. Recent clinical studies reported that ularitide, a synthetic form of urodilatin, secreted by kidney may be effective in managing and treatment of decompensated heart failure. It has also been reported that Nesiritide, a recombinant natriuretic peptide has been proven to improve dyspnea and hemodynamic parameters in heart failure patients. This review provides an update on natriuretic peptides and their therapeutic potential in CHF treatment.

Topics: Angiotensin Receptor Antagonists; Atrial Natriuretic Factor; Biomarkers; Heart Failure; Hemodynamics; Humans; Kidney; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Renin-Angiotensin System

The short- and long-term morbidity and mortality in acute heart failure is still unacceptably high. There is an unmet need for new therapy options with new drugs with a new mode of action. One of the drugs currently in clinical testing in Phase III is ularitide, which is the chemically synthesized form of the human natriuretic peptide urodilatin. Urodilatin is produced in humans by differential processing of pro-atrial natriuretic peptide in distal renal tubule cells. Physiologically, urodilatin appears to be the natriuretic peptide involved in sodium homeostasis. Ularitide exerts its pharmacological actions such as vasodilation, diuresis, and natriuresis through the natriuretic peptide receptor/particulate guanylate cyclase/cyclic guanosine monophosphate pathway. In animal models of heart failure as well as Phase I and II clinical studies in heart failure patients, ularitide demonstrated beneficial effects such as symptom relief and vasodilation, while still preserving renal function. Subsequently, the pivotal acute decompensated heart failure (ADHF) Phase III study, called TRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients with ADHF compared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Clinical Trials as Topic; Disease Models, Animal; Diuretics; Female; Heart Failure; Humans; Male; Peptide Fragments; Rats, Wistar; Vasodilation

Treatment for acutely decompensated heart failure (ADHF) has not changed much in the last two decades. Currently available therapies have variable efficacy and can be associated with adverse outcomes. Natriuretic peptides properties include diuresis, natriuresis, vasorelaxation, inhibition of renin-angiotensin-aldosterone system, and are thus chosen in the treatment of ADHF. Two forms of natriuretic peptides are currently available for the treatment of ADHF. Urodilatin (INN: ularitide) represents another member of the natriuretic peptide family with a unique molecular structure that may provide distinct benefits in the treatment of ADHF. Early clinical exploratory and Phase II studies have demonstrated that ularitide has potential cardiovascular and renal benefits. Ularitide is currently being tested in the Phase III TRUE-AHF clinical study. TRUE-AHF has features that may be different when compared with other recent outcome studies in ADHF. These distinct differences aim to maximize clinical effects and minimize potential adverse events of ularitide. However, whether this rationale translates into a better outcome needs to be awaited.

Topics: Acute Disease; Atrial Natriuretic Factor; Diuretics; Heart Failure; Humans; Peptide Fragments; Treatment Outcome

Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics.

Topics: Amides; Aminobutyrates; Atrial Natriuretic Factor; Biphenyl Compounds; Digoxin; Drug Combinations; Fumarates; Heart Failure; Humans; Natriuretic Peptides; Peptide Fragments; Snake Venoms; Tetrazoles; Valsartan

Acute heart failure is a major cause of emergency hospital admission, with significant impact on health resources and patient outcomes. With no new treatments for over 20 years, the advent of new innovative therapies may facilitate a radical change in our approach to such patients. In this article, we examine the current evidence for the use of current intravenous vasodilators in AHF management, and review the potential of novel therapies currently in development.

Topics: Acute Disease; Administration, Intravenous; Atrial Natriuretic Factor; Benzoates; Heart Failure; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptides; Nitrates; Peptide Fragments; Recombinant Proteins; Relaxin; Snake Venoms; Vasodilator Agents

Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND-HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Blood Pressure Monitoring, Ambulatory; Cardiotonic Agents; Clinical Trials as Topic; Diet, Sodium-Restricted; Diuretics; Dopamine; Dose-Response Relationship, Drug; Dyspnea; Glycopeptides; Heart Failure; Hemofiltration; Hospitalization; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Nitroglycerin; Peptide Fragments; Prognosis; Protein Precursors; Quality of Health Care; Relaxin; Risk Assessment; Saline Solution, Hypertonic; Urea; Vasodilator Agents; Xanthines

Heart failure is an important public health problem that is increasing in prevalence throughout the world. Not only is this condition common, but it is associated with significant morbidity and mortality as well as high costs to medical care systems. Vasodilator drugs help unload the heart and may have other effects that could benefit heart failure patients. Consequently, they have emerged as an important therapeutic approach for patients with this condition. Novel vasodilator therapies that are currently in development target new pathways, potentially giving clinicians alternate options for improving outcomes in this vulnerable population. This review focuses on investigational drugs that have the ability to dilate blood vessels amongst their therapeutic properties. These drugs include the natriuretic peptides that activate particulate guanylate cyclase, the novel agent cinaciguat that activates the soluble guanylate cyclase system, and finally a recombinant form of the naturally occurring vasodilating agent relaxin, a hormone that mediates many of the changes that allows the cardiovascular system to successfully adapt to pregnancy.

Topics: Atrial Natriuretic Factor; Benzoates; Diuretics; Guanylate Cyclase; Heart Failure; Humans; Natriuretic Peptides; Peptide Fragments; Relaxin; Vasodilator Agents

Acute heart failure is a public health issue with morbidity and mortality exceeding that of myocardial infarction. Novel compounds for the treatment of acute heart failure are clearly needed and fall into the general categories of inotropic, vasodilatory and other compounds in phase I to III of development. Furthest along are omecamtiv mecarbil (a cardiac myosin activator), ularitide (a natriuretic and diuretic peptide) and relaxin (a vasodilator). Each compound has a unique set of assets and liabilities that will aid in the understanding of the syndrome and application to the right patients at the right time in this heterogeneous syndrome. This review will explore current and future novel pharmacologic therapies for the treatment of acute heart failure.

Topics: Acute Disease; Atrial Natriuretic Factor; Diuretics; Heart Failure; Humans; Peptide Fragments; Relaxin; Urea; Vasodilator Agents

Heart failure is the most frequent cause of hospitalization in elderly population. Unlike the therapy of congestive heart failure, there was only a modest progress in the medical treatment for acutely decompensated heart failure over the past several decades. Moreover, current treatment is associated with many limitations in clinical practice. The family of natriuretic peptides consists of several structurally similar polypeptides (ANP, BNP, CNP, urodilatin, DNP). ANP and BNP are the most characterized substances and represent an important compensatory mechanisms in heart failure because of their vasodilatory, natriuretic and antiproliferative effects. Nesiritide is a recombinant human BNP which has been shown to be effective in treating heart failure in several clinical trials. However, a recent meta-analysis revealed a nesiritide-associated increased 30-day-mortality rate. The results of initial small-sized trials suggest beneficial hemodynamic effects of urodilatin in decompensated heart failure. Despite of being approved for the treatment of decompensated heart failure in some countries, the clinical relevance of nesiritide is currently unclear. Urodilatin might represent a potential alternative.

Topics: Acute Disease; Atrial Natriuretic Factor; Diuretics; Drug Approval; Heart Failure; Hemodynamics; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Rate

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

Topics: Acute Disease; Atrial Natriuretic Factor; Benzoates; Elapid Venoms; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nitrates; Peptide Fragments; Prognosis; Pyridines; Receptors, Endothelin; Relaxin; Tetrazoles; Vasoconstriction; Vasodilator Agents

In this review we investigate the role of particulate and soluble guanylate cyclase (pGC and sGC, respectively) pathways in heart failure, and several novel drugs that modify guanylate cyclase. Nesiritide and ularitide/urodilatin are natriuretic peptides with vasodilating, natriuretic and diuretic effects, acting on pGC, whilst cinaciguat (BAY 58-2667) is a novel sGC activator. Cinaciguat has a promising and novel mode of action because it can stimulate cyclic guanosine-3',5'-monophosphate synthesis by targeting sGC in its nitric oxide-insensitive, oxidised ferric (Fe(3+)) or haem-free state. Thus, cinaciguat may also be effective under oxidative stress conditions resulting in oxidised or haem-free sGC refractory to traditional organic nitrate therapies. Preliminary studies of cinaciguat in patients with acute decompensated heart failure show substantial improvements in haemodynamics and symptoms, whilst maintaining renal function.

Topics: Animals; Atrial Natriuretic Factor; Benzoates; Creatinine; Disease Progression; Diuretics; Dose-Response Relationship, Drug; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Natriuretic Peptide, Brain; Oxidative Stress; Peptide Fragments

Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.

Topics: Atrial Natriuretic Factor; Cardiovascular Agents; Clinical Trials as Topic; Cyclic GMP; Drug Therapy, Combination; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptide Fragments; Receptors, Atrial Natriuretic Factor; Snake Venoms; Treatment Outcome

The kidney natriuretic peptide urodilatin (ie, ularitide) decreases pulmonary capillary wedge pressure (PCWP) but does not cause diuresis in persons with congestive heart failure (CHF). Thirty-three percent of patients with CHF treated with 30 ng/kg/min ularitide develop hypotension with systolic blood pressures below 90 mmHg. Nesiritide and atrial natriuretic peptide lower PCWP and cause hypotension. They do not produce diuresis or natriuresis in patients with CHF. The best natriuretic peptide for treating CHF is the cardiac hormone vessel dilator which decreases PCWP and decreases systemic and pulmonary vascular resistance while simultaneously increasing cardiac output and cardiac index. What makes the vessel dilator markedly better than atrial natriuretic peptide, nesiritide, and ularitide for treatment of CHF is that it enhances sodium excretion fivefold and causes a fivefold enhanced diuresis in patients with CHF with its biologic effects lasting over 6 hours compared with less than 30 minutes for the above peptides.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Diuresis; Diuretics; Heart Failure; Humans; Peptide Fragments; Prognosis; Vasodilation

While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.

Topics: Antidiuretic Hormone Receptor Antagonists; Atrial Natriuretic Factor; Cardiac Myosins; Cardiotonic Agents; Cardiovascular Agents; Etiocholanolone; Heart Failure; Humans; Natriuretic Agents; Peptide Fragments; Perhexiline; Purinergic P1 Receptor Antagonists; Sodium-Potassium-Exchanging ATPase

A renal natriuretic peptide and the 'renal urodilatin system' were identified after the observation that immunoassayable ANP in urine may not be identical to the circulating cardiac hormone ANP, which is a peptide of 28 amino acids. Urodilatin (INN: Ularitide) is a natriuretic peptide isolated from human urine and belongs to the family of A-type natriuretic peptides. Urodilatin is differentially processed to a peptide of 32 amino acids from the same precursor as ANP. It is synthesized in kidney tubular cells and secreted luminally. After secretion from epithelial cells of the distal and/or connecting tubules, Urodilatin interacts downstream at distal segments of the nephron with luminally located receptors whereby it regulates Na(+) and water reabsorption. Thus, the physiological function of the renal Urodilatin system can be described as a paracrine intrarenal regulator for Na(+) and water homeostasis, considering Urodilatin as a real diuretic-natriuretic regulatory peptide. However, the regulation upon which the Urodilatin secretion depends is still not clear. Since Urodilatin has been discovered, a great number of pharmacological and clinical investigations have been carried out using Urodilatin as a drug for several indications. So far, clinical phase I and II studies for acute renal failure, congestive heart failure, and bronchial asthma have been performed.

Topics: Animals; Asthma; Atrial Natriuretic Factor; Bronchodilator Agents; Diuresis; Diuretics; Heart Failure; Humans; Peptide Fragments

Natriuretic peptides (NP) constitute hormonal systems of great clinical impact. This report deals with Urodilatin (URO), a renal natriuretic peptide type A. From the gene of NP type A, a message for the preprohormone is transcribed in heart and kidney. The cardiac prohormone CDD/ANP-1-126 is synthesized in the heart atrium and processed during exocytosis forming the circulating hormone CDD/ANP-99-126. URO (CDD/ANP 95-126) is a product from the same gene, but differentially processed in the kidney and detected only in urine. Physiologically, URO acts in a paracrine fashion. After release from distal tubular kidney cells into the tubular lumen, URO binds to luminal receptors (NPR-A) in the collecting duct resulting in a cGMP-dependent signal transduction. cGMP generation is followed by an interaction with the amiloriode-sensitive sodium channel which induces diuresis and natriuresis. In this way, URO physiologically regulates fluid balance and sodium homeostasis. Moreover, URO excretion and natriuresis are in turn dependent on several physiological states, such as directly by sodium homeostasis. Pharmacologically, URO at low dose administered intravenously shows a strong diuretic and natriuretic effect and a low hypotensive effect. Renal, pulmonary, and cardiovascular effects evoked by pharmacological doses indicate that URO is a putative drug for several related diseases. Clinical trials show promising results for various clinical indications. However, the reduction in hemodialysis/hemofiltration in patients suffering from ARF following heart and liver transplantation, derived from preliminary trials recruiting a small number of patients, was not confirmed by a multicenter phase II study. In contrast, data for the prophylactic use of URO in this clinical setting suggest a better outcome for the patients. Furthermore, treatment of asthmatic patients showed a convincingly beneficial effect of URO on pulmonary function. Patients with congestive heart failure may also profit from URO treatment, as it increases stroke volume and PCWP. Moreover, preliminary results from recent studies indicate that URO may also be effective in patients suffering from hepato-renal syndrome.

Topics: Acute Kidney Injury; Amino Acid Sequence; Atrial Natriuretic Factor; Diuretics; Heart Failure; Hepatorenal Syndrome; Humans; Molecular Sequence Data; Peptide Fragments; Second Messenger Systems

Topics: Acute Kidney Injury; Amino Acid Sequence; Animals; Asthma; Atrial Natriuretic Factor; Bronchodilator Agents; Heart Failure; Humans; Lung; Molecular Sequence Data; Neuropeptides; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Vasodilator Agents

Atrial natriuretic peptide (ANP) exhibits a favorable pharmacological profile in heart failure. In reduces preload and afterload by its natriuretic and vasodilatatory actions. Furthermore, it reduces the activity of the renin aldosterone system. This peptide is activated in early heart failure. Plasma levels of 1-28-hANP are elevated and they correlate with the clinical stage of heart failure, as well as with hemodynamic abnormalities. However, the efficacy of this cardiac hormone in heart failure is limited by renal resistance. Possible mechanisms are a reduced renal perfusion pressure, a receptor down-regulation or an overactivity of sodium-retaining hormones like the renin aldosterone system, and the sympathetic activity. The brain natriuretic peptide (BNP) is also stimulated in heart failure; however, its role in the pathophysiology of heart failure remains to be determined.

Topics: Animals; Atrial Natriuretic Factor; Heart Failure; Hemodynamics; Humans; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Structure-Activity Relationship

In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis.. In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course.. Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data.. In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634 .).

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiovascular Diseases; Diuretics; Double-Blind Method; Female; Follow-Up Studies; Heart Failure; Humans; Hypotension; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Troponin T

Renal function frequently deteriorates in decompensated heart failure (DHF) patients, and one determinant is reduced renal blood flow. This may, in part, result from low cardiac output (CO), reduced mean arterial pressure (MAP), and venous congestion. The combined impact of both venous congestion (elevated right atrial pressure [RAP]) and low MAP are reflected by a reduced pressure gradient MAP-RAP. This study investigated the renal effects of ularitide, a synthetic version of the renal natriuretic peptide urodilatin in DHF patients.. In SIRIUS II, a double-blind phase II trial, 221 patients hospitalized for DHF (with dyspnea at rest or minimal activity, cardiac index or=18 mm Hg) were randomized to a single 24-hour infusion of ularitide (7.5, 15, or 30 ng/kg per minute) or placebo added to standard therapy.. Estimated glomerular filtration rate, serum creatinine, creatinine clearance, and blood urea nitrogen (BUN) were not impaired by ularitide throughout infusion and during a 2-day follow-up period. At 24 hours, 15 ng/kg per minute ularitide reduced BUN levels (-4.07 +/- 12.30 vs -0.20 +/- 7.50 for placebo, P < .05). Ularitide at 15 and 30 ng/kg per minute rapidly elevated CO with sustained effects. Although 15 ng/kg per minute ularitide preserved the pressure gradient MAP-RAP, 30 ng/kg per minute ularitide reduced MAP-RAP by -7.8 +/- 10.6 mm Hg vs -2.4 +/- 9.8 mm Hg for placebo (P < .01, at 6 hours). A strong inverse correlation between MAP-RAP and BUN levels (Corr = -0.50579, P = .00015) was observed with 15 ng/kg per minute ularitide.. Single 24-hour infusions of ularitide at 15 ng/kg per minute preserved short-term renal function in DHF patients possibly by both elevating CO and maintaining the MAP-RAP pressure gradient.

Topics: Aged; Atrial Natriuretic Factor; Creatinine; Diuretics; Double-Blind Method; Female; Glomerular Filtration Rate; Heart Failure; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Peptide Fragments; Severity of Illness Index

Ularitide is a synthetic form of urodilatin, a natriuretic peptide produced in the kidney with vasodilating, natriuretic, and diuretic effects, that offers promise for the management of decompensated heart failure (DHF). We assessed the efficacy and safety of ularitide in treating patients with DHF.. In this Phase II randomized, double-blind, placebo-controlled trial, 221 DHF patients received either placebo (n=53) or ularitide at 7.5 ng/kg/min (n=60), 15 ng/kg/min (n=53), or 30 ng/kg/min (n=55) as a 24-h continuous infusion. At 6 h, ularitide demonstrated a significant decrease in pulmonary capillary wedge pressure (P=0.052, P=0.000004, P=0.000002, respectively) and improved dyspnoea score in the 7.5, 15, and 30 ng/kg/min ularitide group (P=0.0026, P=0.0026, P=0.0013, respectively). Ularitide reduced systemic vascular resistance and increased cardiac index for the 15 and 30 ng/kg/min groups (P=0.017, P=0.00002, respectively). Systolic blood pressure (BP) decreased dose dependency. Heart rate and serum creatinine were unchanged through day 3. Most frequently reported drug-related adverse events through day 3 in all ularitide groups were dose-dependent BP decrease and hypotension.. Ularitide lowered cardiac filling pressures and improved dyspnoea without apparent early deleterious effects on renal function in DHF patients. These results suggest that ularitide may play a role in the management of DHF.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Failure; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Peptide Fragments; Urination; Vascular Resistance; Vasodilator Agents

Urodilatin (ularitide), a natriuretic peptide, is produced within the kidneys. The aim of this study was to define the role of 24-hour intravenous infusions of urodilatin in the treatment of decompensated chronic heart failure (DHF).. In this randomized, double-blind, ascending-dose safety study, 24 patients with DHF (cardiac index 1.91 +/- 0.34 L/min per square meter, pulmonary capillary wedge pressure 26 +/- 6 mm Hg, right atrial pressure 11 +/- 4 mm Hg) received urodilatin (7.5, 15, or 30 ng/(kg.min)) or placebo infusions over 24 hours.. Compared with baseline, urodilatin decreased pulmonary capillary wedge pressure by 10 mm Hg in the 15 ng/(kg.min) group (P < .05) and by 15 mm Hg in the 30 ng/(kg.min) group (P < .05) at 6 hours. In the same dose groups, right atrial pressure decreased, and dyspnea as reported by patients tended to improve. At 24 hours, 15 and 30 ng/(kg.min) urodilatin infusions decreased N-terminal-pro-brain natriuretic peptide levels by 40% and 45%, respectively, compared with baseline. Between 1 to 12 hours, plasma cyclic guanosine monophosphate levels at 15 and 30 ng/(kg.min) urodilatin were significantly higher than both placebo and the respective baseline after infusion start (P < .05 and .01). Among the different groups, there was no obvious difference regarding total number of patients with adverse events and total number of adverse events. During infusion, 3 transient asymptomatic hypotensions occurred in the urodilatin groups.. Our findings show that urodilatin may be a new agent for the therapy for DHF.

Topics: Aged; Atrial Natriuretic Factor; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Failure; Heart Function Tests; Humans; Kidney; Male; Middle Aged; Patient Selection; Peptide Fragments; Placebos; Respiratory Function Tests

Urodilatin [ANP-95-126] is a new natriuretic peptide of renal origin not subjected to tolerance in experimental congestive heart failure (CHF). To evaluate its therapeutic potentials in CHF, we investigated the efficacy of a prolonged infusion of urodilatin (15 ng/kg/min for 10 hours) in 12 patients with CHF (New York Heart Association functional classes II and III) in a randomized, double-blind, placebo-controlled study. Urodilatin elevated plasma cyclic guanosine monophosphate (cGMP) concentrations and increased urinary cGMP excretion. Systolic blood pressure (121 +/- 9 mm Hg to 111 +/- 7 mm Hg) and central venous pressure (7.4 +/- 3.3 mm Hg to 5.2 +/- 3.4 mm Hg) decreased significantly, and diastolic blood pressure and heart rate remained unchanged. Urine flow (0.7 +/- 0.6 ml/min to 1.5 +/- .6 ml/min) and urinary sodium excretion (48 +/- 16 mumol/min to 180 +/- 97 mumol/min) were significantly increased. Plasma norepinephrine, renin, aldosterone, and vasopressin were unaltered. The substance was well tolerated. Thus prolonged infusion of urodilatin lowers preload and increases diuresis and natriuresis without neurohumoral activation or adverse side effects, demonstrating a profile of effects that may be beneficial in patients with CHF.

Topics: Aged; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Diuretics; Double-Blind Method; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Peptide Fragments; Renin; Time Factors

Urodilatin (ANF(95-126)) is an analogue of the atrial natriuretic factor (ANF(99-126)), which has been isolated from human urine. Recently we have shown in healthy volunteers, that intravenous bolus injections of synthetic urodilatin produce more pronounced reductions of pulmonary arterial pressure than ANF(99-126). To compare haemodynamic and renal effects of synthetic urodilatin with those of ANF(99-126) in congestive heart failure (CHF), 12 patients (66.3 +/- 1.4 years) received either two high dose intravenous bolus injections of 4 micrograms kg-1 bw Urodilatin (URO) at a 30 min interval (n = 6) or the same doses of ANF(99-126) (n = 6). Prior to i.v. URO, no URO immunoreactivity was found in human plasma (specific RIA, no crossreactivity to ANF). Similar to ANF, the increase in diuresis (1.4 +/- 0.7 to 3.7 +/- 1.6 ml min-1) and natriuresis (169 +/- 114 to 430 +/- 197 mumol min-1) was moderate after URO in CHF. During the 90 min study period, mean plasma cyclic GMP levels increased much more after URO (by 53.4 +/- 15.1 nM) than after ANF (by 13.1 +/- 3.0 nM; P = 0.04). In contrast to ANF, i.v. bolus injections of URO produced sustained haemodynamic effects in CHF lasting up to 90 min: The average (0-90 min) reduction of systemic vascular resistance was more pronounced after URO (-578 +/- 148) than after ANF (-204 +/- 65 dyn*s*cm-5, P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Amino Acid Sequence; Atrial Natriuretic Factor; Creatinine; Cyclic GMP; Diuretics; Female; Heart Failure; Hemodynamics; Humans; Injections, Intravenous; Kidney; Male; Middle Aged; Molecular Sequence Data; Peptide Fragments

The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure.. NCT01661634.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Diuretics; Double-Blind Method; Drug Administration Schedule; Female; Global Health; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Peptide Fragments; Survival Rate; Treatment Outcome; Young Adult

16th Annual Autumn Meeting of the British Society of Heart Failure: 'Making sense of acute heart failure', London, UK, 28-29 November 2013 The 16th Annual Autumn Meeting of the British Society of Heart Failure entitled 'Making sense of acute heart failure' took place on the 28-29 November 2013 at the Queen Elizabeth II Conference Centre in London. This year saw the 1000th member join the British Society of Heart Failure and over 700 delegates from the UK, Europe and North America attended this year's meeting. Professionals from a range of backgrounds were present including physicians, nurses, scientists, trainees and representatives from industry. The symposium, which is accredited by the Royal College of Physicians and the Royal College of Nursing, highlighted that although we have recently seen substantial progress in the management and outcomes of patients with chronic heart failure, acute heart failure management and outcomes have not changed significantly over almost a generation.

Topics: Atrial Natriuretic Factor; Clinical Audit; Clinical Trials as Topic; Comorbidity; Diuretics; Heart Failure; Hospitalization; Humans; Patient Care Team; Peptide Fragments; Stroke Volume; United Kingdom

Topics: Animals; Atrial Natriuretic Factor; Calcineurin; Heart Failure; Humans; Hypertension; Models, Animal; Myocytes, Cardiac; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptides; Peptide Fragments; Rats; Recombinant Fusion Proteins; Signal Transduction; Sodium-Hydrogen Exchangers; Ventricular Remodeling

Acute decompensated heart failure is a growing public health care problem worldwide. The goals of treatment are immediate hemodynamic and symptomatic improvement followed by persistent follow-up with adherence to chronic heart failure guidelines. Controversies have centered around the best treatment options and avoidance of serious adverse events. This article highlights our current understanding of acute decompensated heart failure, discusses the controversy surrounding currently available new vasoactive treatments, and details future potential therapies.

Topics: Acute Disease; Atrial Natriuretic Factor; Diuretics; Guideline Adherence; Heart Failure; Humans; Hydrazones; Natriuretic Peptide, Brain; Peptide Fragments; Practice Guidelines as Topic; Pyridazines; Randomized Controlled Trials as Topic; Simendan; Vasodilator Agents

A hallmark of overt congestive heart failure (CHF) is attenuated cGMP production by endogenous atrial natriuretic peptide (ANP) with renal resistance to ANP. ANP and brain natriuretic peptides (BNP) are of myocardial origin, whereas urodilatin (Uro) is thought to be derived from kidney. All three peptides are agonists to the natriuretic peptide-A receptor. Our objective was to compare the cardiorenal and humoral actions of ANP, BNP, and Uro in experimental overt CHF. We determined cardiorenal and humoral actions of 90 min of intravenous equimolar infusion of ANP, BNP, and Uro (2 and 10 pmol.kg-1.min-1) in three separate groups of anesthetized dogs with rapid ventricular pacing-induced overt CHF (240 beats/min for 10 days). BNP resulted in increases in urinary sodium excretion (U(Na)V) (2.2+/-0.7 to 164+/-76 microeq/min, P<0.05) and glomerular filtration rate (GFR) (27+/-4 to 52+/-11 ml/min, P<0.05) that were greater than those with Uro (P<0.05), whereas ANP did not result in increases in U(Na)V or GFR. Increases in plasma cGMP (25+/-2 to 38+/-2 pmol/ml, P<0.05) and urinary cGMP excretion with BNP (1,618+/-151 to 6,124+/-995 pmol/min, P<0.05) were similar to those with Uro; however, there was no change with ANP. Cardiac filling pressures were reduced in all three groups. These studies also support the conclusion that in experimental overt CHF, renal resistance to natriuretic peptides in increasing rank order is BNP

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Heart Failure; Hemodynamics; Kidney; Male; Natriuretic Peptide, Brain; Peptide Fragments

Natriuretic peptides (NPs) reduce central venous pressure in patients with chronic heart failure (cHF) despite attenuation of arterial, renal, and humoral effects. This suggests a preserved venodilator response. This study had 4 aims: to compare the venodilator effects of human NPs in patients with cHF; to assess the contribution of basal ANP and BNP levels to regulation of forearm vascular volume (FVV); to test the hypothesis that venous ANP responsiveness is preserved in cHF; and to assess the involvement of endothelial nitric oxide-synthase (eNOS) in NP-induced vascular effects.. Venous and arterial forearm vascular responses to incremental intra-arterial doses of ANP, Urodilatin, BNP, CNP, or the ANP receptor antagonist A71915 were studied in 53 patients and 11 controls. ANP receptor antagonism reduced FVV by 4.4%+/-1.2% (P<0.05). The forearm blood flow (FBF) response to ANP was significantly blunted in patients versus controls (P<0.01), whereas FVV increased similarly in both groups (maximum 14.7% and 13.4%, both P<0.001). The eNOS blockade reduced ANP-induced FBF changes in controls but not in patients (P<0.05), whereas similar reductions in FVV changes were seen in groups (both P<0.001).. In cHF venous, but not arterial, ANP responsiveness is preserved. Arterial endothelial dysfunction may contribute to NP resistance.

Topics: Adult; Aged; Aged, 80 and over; Arteries; Atrial Natriuretic Factor; Cardiovascular Agents; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Female; Forearm; Heart Failure; Humans; Injections, Intra-Arterial; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Peptide Fragments; Tetrahydroisoquinolines; Vascular Resistance; Vasodilation; Veins

Accumulating evidence suggests that urodilatin, a kidney-derived member of the natriuretic peptide family, contributes as a major mediator of sodium excretion to body fluid regulation in healthy men. In contrast to other members of the natriuretic peptide family, pathophysiological data for the renal natriuretic peptide have still been missing. The present study compares renal synthesis of urodilatin in patients with congestive heart failure (CHF) and healthy volunteers. Because urodilatin excretion, considerably increases with increasing nutritive sodium intake (p<0.004), the CHF patients (15 NYHA I/II, 8 NYHA III/IV) were kept on a 165 mmol/day sodium diet and 6 healthy volunteers on a identical nutritive sodium intake level were selected as proper controls. Although urodilatin excretion significantly increased (p<0.027) with increasing severity of CHF and was therefore significantly higher in mild CHF (40.7 +/- 2.5 fmol/min) and severe CHF (54.7 +/- 6.6 fmol/min) than in healthy controls (3.2 +/- 4.2 fmol/min), both groups of CHF patients retained sodium and had significantly lower sodium excretion rates (NYHA I/II 79.0 +/- 6.9 micromol/min, NYHA III/IV 97.9 +/- 12.7 micromol/min) than the healthy controls (139 +/- 3.4 micromol/min). Our data suggest that renal urodilatin synthesis, may not be involved in the etiology of sodium retention in CHF, but may rather be stimulated to counteract antinatriuresis during CHF.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Child; Child, Preschool; Cyclic GMP; Diuretics; Female; Heart Failure; Humans; Male; Middle Aged; Peptide Fragments; Sodium; Sodium, Dietary

The effects of a continuous i.v. infusion of urodilatin at a dose of 30 ng kg-1 min-1 were studied in a patient with congestive heart failure. After 30 min, urodilatin had induced a marked stimulation of plasma cyclic GMP concentrations. In parallel haematocrit increased. No significant diuresis and no change of invasive haemodynamics was observed. After 2 h the patient developed a profuse perspiration. Eighty minutes later he suffered from dizziness due to hypotension (blood pressure 80/40 mmHg) and a sudden bradycardia (50 bpm). Urodilatin was discontinued and symptoms were relieved by bed tilt and rapid infusion of isotonic saline solution. Mechanisms contributing to these adverse effects may be fluid extravasation to the third space and sympathoinhibitory effects known to occur with natriuretic peptide infusion.

Topics: Atrial Natriuretic Factor; Blood Pressure; Bradycardia; Cardiac Output; Cyclic GMP; Heart Failure; Heart Rate; Hematocrit; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Peptide Fragments

Urodilatin is a recently discovered natriuretic peptide [ANP-(95-126)] of renal origin, with a primary structure similar to ANP-(99-126). However, urodilatin is not biologically inactivated by renal endopeptidase, and it is a more potent natriuretic agent than ANP-(99-126). The present study was carried out to investigate the renal and systemic effects of urodilatin in rats before and after the induction of congestive heart failure (CHF) by creation of an aortocaval fistula (ACF). Administration of urodilatin in incremental doses (0.75-12 micrograms.kg-1.h-1) to Inactin-anesthetized sham-operated control rats resulted in dose-dependent increases in urine flow, glomerular filtration rate (GFR), excretion of guanosine 3',5'-cyclic monophosphate (cGMP), sodium, and potassium, and a significant decrease in mean arterial blood pressure. In rats with ACF the baseline values for GFR and sodium excretion were significantly lower than in control rats. Urodilatin infusion in rats with ACF led to significant increases in urine flow and sodium excretion, but the absolute levels of diuresis and natriuresis were significantly lower in rats with CHF than in normal rats. When urodilatin was infused into rats with ACF pretreated with neutral endopeptidase inhibitor (NEP-I; SQ-28,063 at a dose of 40 mg/kg iv), the absolute urine flow and sodium excretion were not different from that obtained in control rats. Thus the attenuated natriuretic and diuretic response to ANP-(99-126) in heart failure was not observed with urodilatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output; Diuretics; Dose-Response Relationship, Drug; Drug Combinations; Heart Failure; Kidney; Male; Neprilysin; Peptide Fragments; Rats; Rats, Inbred Strains

Topics: Aged; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Female; Heart Failure; Hemodynamics; Humans; Male; Peptide Fragments